Our recent studies reveal an increased prevalence of coronary heart disease (CHD) in Japanese-American men with mutations in the cholesteryl ester transfer protein (CETP) gene despite increased HDL levels. Similarly, we have observed a decrease in early atherosclerosis in CETP transgenic (Tg) mice with decreased HDL levels. Together these findings suggest that the dominant effects of CETP expresssion in vivo may be anti-atherogenic. However, the anti-atherogenic effects of CETP expression in Tg mice were only observed int he context of hypertriglyceridemia due to apoCIII transgene expression. The overall goals are to evaluate further the relationship of CETP and HDL to atherogenesis in humans and mice and to define the underlying mechanisms. The specific aims are 1) to assess effects of CETP expression on atherogenesis in susceptible apoB Tg mice and to define underlying mechanisms related to hypertriglyceridemia or reverse cholesterol transport; 2) to evaluate novel anti-atherogenic effects of CETP and HDL mediated at the level of the arterial wall in apoB Tg mice with expression CETP in arterial wall cells or apoA-I overexpression or diabetes; and 3) to investigate mechanisms responsible for increased CHD in human genetic CETP deficiency, to identify common variants of CETP or hepatic lipase genes and to relate variants to CHD. The proposed research involves collaborations with Projects 1 9effects of HDL/CETP on LDL aggregation and arterial retention), 2 (relationship of lipoprotein size and apoCIII gene variation to VLDL arterial influx and atherogenesis), 4 (effects of HDL and lipid transfer on atherogenesis in diabetic mice) and 5 (role of HDL in mediating decreased atherogenesis in interferon-gamma receptor 0/apoE0 mice); and uses the Molecular Biology Core for development of Tg mice and for genotyping human DNA samples, the Pathology Core for the characterizaiton and quantitation of atherosclerotic lesions in mice and the Clinical/Biostatistics Core for human studies. The project is tied to two major SCOR themes: the use of induced mutant mice to investigate mechanisms of atherogenesis in the vessel wall and the identification of gene variants that provide novel information on human CHD risk.